The Coming Plague

by Laurie Garrett

  123 National Institutes of Allergy and Infectious Diseases, State-of-the-Art Conference on Antiretroviral Therapy, Bethesda, MD, June 23–25, 1993.

  124 F. G. Hayden, R. B. Belshe, R. D. Clover, et al., “Emergence and Apparent Transmission of Rimantadine-Resistant Influenza A Virus in Families,” New England Journal of Medicine 321 (1989): 1696–1702; and R. B. Belshe, M. H. Smith, C. B. Hall, et al., “Genetic Basis of Resistance to Rimantadine Emerging During Treatment of Influenza Virus Infection,” Journal of Virology 62 (1988): 1508–12.

  125 Doctors relied almost entirely upon drug companies, directly or indirectly, for advice about use of antibiotics. The companies spent $11 billion a year in the United States alone promoting use of their products. For busy physicians who hadn’t the time to sift through medical literature to learn of contrary evidence, it was hard to resist the alluring pull of pharmaceutical promotions. See R. L. Woosley, “A Prescription for Better Prescriptions,” Issues in Science and Technology (Spring 1994): 59–66.

  126 World Bank, World Development Report 1993: Investing in Health (New York: Oxford University Press, 1993).

  127 A. J. Slater, “Antibiotic Resistance in the Tropics,” Transactions of the Royal Society of Tropical Medicine and Hygiene 83 (1989): 45–48.

  128 A. Chetley, “Bangladesh Drug Policy Hanging in the Balance,” Lancet 343 (1994): 967.

  129 For analyses of drug development policies and politico-economic conflict, see D. E. Bell and M. R. Reich, Health, Nutrition, and Economic Crises: Approaches to Policy in the Third World (Dover, MA: Auburn House. 1988); Pan American Health Organization, Policies for the Production and Marketing of Essential Drugs (Washington, D.C., 1984); M. R. Reich, “Essential Drugs: Economics and Politics in International Health,” Health Policy 8 (1987): 39–57; and World Bank, Financing Health Services in Developing Countries: An Agenda for Reform (Washington, D.C.: World Bank, 1987).

  130 P. Lepage, J. Bogarts, C. Van Goethem, et al., “Community-Acquired Bacteraemia in African Children,” Lancet I (1987): 1458–61.

  131 Corruption and black marketeering were critical problems for antibiotic distribution and misuse in developing countries. In many parts of the world untrained medical “injectionists” earned a living by injecting illegally obtained antibiotics and vitamins into customers, often in the major marketplaces in full view of police. Needles and the medicinal drugs were, therefore, of very high value. Such misuse of the drugs no doubt contributed both to resistance and to lack of supplies for diarrheal epidemics.

  The following wire story release from the Associated Press in July 1993 illustrated the problem:

  NAIROBI, KENYA (AP)—Patients bring their own medicine, food and syringes to some government hospitals because employees often steal and sell what few supplies are issued.

  Inflation is soaring, partly because the government printed billions of new shillings last year to finance the ruling party’s campaign and bribe voters.

  Much of the social security fund was lost when officials illegally put it into real estate deals and other bad investments. Asked by journalists whether anyone would be held accountable, Treasury Secretary Wilfred Koinange replied: “What do you want, heads to roll?”

  132 An excellent summary of the ivermectin saga is in E. Tanouye, “Merck’s ‘River Blindness’ Gift Hits Snag,” Wall Street Journal, September 23, 1992: A1, B7. Merck was able to reap ample profits off veterinary use of ivermectin: annual sales topped the $500 million mark in 1990, according to the World Bank.

  133 See, for example, W. C. Hsiao, “Lessons for Developing Countries from the Experiences of Affluent Nations About a Comprehensive Health Financing Strategy,” presented at International Seminar on Comprehensive Financing Strategy in Select Asian Nations, December 10–14, 1990, Bali, Indonesia.

  134 International Federation of Pharmaceutical Manufacturers Associations, The Pharmaceutical Industry: International Issues and Answers (Washington, D.C.: Pharmaceutical Manufacturers Association, 1979).

  135 See, for example, S. Lall and S. Bibile, “The Political Economy of Controlling Transnationals: The Pharmaceutical Industry in Sri Lanka, 1972–1976,” International Journal of Health Services 8 (1978): 299–328: T. Heller, Poor Health, Rich Profits: Multinational Drug Companies and the Third World (London: Spokesman Books, 1977); UNCTAD Secretariat, “Dominant Positions of Market Power of Transnational Corporations: Use of the Transfer Pricing Mechanism,” Geneva, November 30, 1977; J. M. Starrels, “The World Health Organization, Resisting Third World Ideological Pressures” (Washington, D.C.: Heritage Foundation, 1985); R. Deitch, “Commentary from Westminster: More Pressure on the Profits of the Pharmaceutical Industry,” Lancet I (1984): 521; and International Federation of Pharmaceutical Manufacturers Associations (IFPMA), “Medicines and the Developing World,” Geneva, 1984.

  136 S. Kingman, “Malaria Runs Riot on Brazil’s Wild Frontier,” New Scientist, August 12, 1989: 24–25.

  137 World Health Organization, “Malaria Worsening in Many Areas,” PR/WHA/6/May 9, 1991, Geneva.

  138 P. G. Kremsner, G. M. Zotter, H. Feldmeier, et al., “In vitro Drug Sensitivity of Plasmodium falciparum in Acre, Brazil,” Bulletin of the World Health Organization 67 (1989): 289–93; and S. Reyes, C. H. Osanai, and A. D. Passos, “In vivo Resistance of Plasmodium falciparum to 4-Aminoquinolones and to Sulfadoxine-Pyrimethamine Combination: II. Study of Manaus, Amazonas, 1983–84,” Revista Brasileira de Malariologia e Doenças Tropicais 38 (1986): 37–44.

  139 American Association for the Advancement of Science, Malaria and Development in Africa: A Cross-Sectional Approach, No. AFR-0481-A-00-0037-00, U.S. Agency for International Development, Africa Bureau, Washington, D.C., 1991.

  140 Centers for Disease Control, “Chloroquine-Resistant Malaria Acquired in Kenya and Tanzania: Denmark, Georgia, New York,” Morbidity and Mortality Weekly Report 27 (1978): 463–64; B. H. Kean, “Chloroquine-Resistant falciparum Malaria from Africa,” Journal of the American Medical Association 241 (1979): 395–96; and C. C. Campbell, W. Chin, W. E. Collins, et al., “Chloroquine-Resistant Plasmodium falciparum from East Africa: Cultivation and Drug Sensitivity of the Tanzanian I/CDC Strain from an American Tourist,” Lancet II (1979): 1151–54.

  141 H. C. Spencer, S. C. Masaba, and D. Kiaraho, “Sensitivity of Plasmodium falciparum Isolates to Chloroquine in Kisumu and Malindi, Kenya,” American Journal of Tropical Medicine and Hygiene 31 (1982): 902–6.

  142 W. M. Watkins, D. G. Sixsmith, H. C. Spencer, et al., “Effectiveness of Amodiaquine as Treatment for Chloroquine-Resistant Plasmodium falciparum Infections in Kenya,” Lancet I (1984): 357–59.

  143 D. Overbosch, A. W. vanden Wall Bake, P. C. Stuiver, and H. J. van der Kaay, “Chloroquine-Resistant falciparum Malaria from Malawi,” Tropical and Geographic Medicine 36 (1984): 71–72.

  144 A. M. Blumenfeld, W. L. Sieling, A. Davidson, and M. Isaacson, “Probable Chloroquine-Resistant Plasmodium falciparum Malaria in South-Western Africa,” South African Medical Journal 66 (1984): 207–8.

  145 K. R. Perry, N. M. Hone, and J. M. Cairns, “Chloroquine Resistant Plasmodium falciparum Malaria Confirmed by in-vitro Testing in a District Hospital,” Medical Journal of Zambia 18 (1984): 8–9.

  146 J. Linberg, T. Sandberg, B. Bjorkholm, and A. Bjorkman, “Chloroquine and Fansidar Resistant Malaria Acquired in Angola,” Lancet I (1985): 765.

  147 N. J. Visagie and W. L. Sieling, “Chloroquine-Resistant Plasmodium falciparum Malaria in South Africa: A Case Report,” South African Medical Journal 68 (1985): 600–1.

  148 G. Charmot, J. Le Bras, P. Sansonetti, et al., “Eight Cases of Drug-Resistant Plasmodium falciparum
Malaria Contracted in Mozambique,” Bulletin de la Société de Pathologie Exotique et de Ses Filiales 78 (1985): 500–4.

  149 C. C. Draper, G. Brubaker, A. Geser, and V. A. E. B. Kilimali, “Serial Studies on the Evolution of Chloroquine Resistance in an Area of East Africa Receiving Intermittent Malaria Chemosuppression,” Bulletin of the World Health Organization 63 (1985): 109–18.

  150 P. Nguyen-Dinh, “Etudes sur la Chimioresistance de Plasmodium falciparum en Afrique: Donnees Actuelles,” Annals de la Société Belgique de Médecine Tropique 65 (1985): Suppl. 2, 105–13.

  151 “Chloroquine-Resistant Malaria in Africa,” Lancet I (1985): 1487–88; and H. C. Spencer, D. C. O. Kaseje, A. D. Brandling-Bennett, et al., “Changing Response to Chloroquine of Plasmodium falciparum in Sarididi, Kenya, from 1981 to 1984,” Annals of Tropical Medicine and Parasitology 81 (1987): Suppl. 98–104.

  152 A. Björkman, M. Willcox, N. Marbiah, and D. Payne, “Susceptibility of Plasmodium falciparum to Different Doses of Quinine in vivo and to Quinine and Quinidine in vitro in Relation to Chloroquine in Liberia,” Bulletin of the World Health Organization 69 (1991): 459–65.

  153 “One Bite Is Too Many,” The Economist, August 21, 1993: 33–34; and American Association for the Advancement of Science (1991), op. cit.

  154 Ibid.

  Similar observations were made from one end of the continent to the other. In Brazzaville, for example, cerebral malaria in children soared between January 1988 and June 1989, as did chloroquine resistance. Fifteen percent of the cases were immediately lethal. And a third of the survivors went on to suffer debilitating ailments, such as periodic convulsions, as a result of fever damage to their brains. See B. Carme, J. C. Bouquetry, and H. Plassart, “Mortality and Sequelae Due to Cerebral Malaria in African Children in Brazzaville, Congo,” American Journal of Tropical Medicine and Hygiene 48 (1993): 216–21.

  Even more striking were the escalating malaria admissions to hospitals in Kinshasa. Between 1982 and 1986 the percentage of all pediatric admissions that were due to acute malaria rose from 29.5 percent to 56.4 percent. See A. E. Greenberg, M. Ntumbanzondo, N. Ntula, et al., “Hospital-Based Surveillance of Malaria-Related Paediatric Morbidity and Mortality in Kinshasa, Zaire,” Bulletin of the World Health Organization 67 (1989): 186–9.

  155 During that time, malaria incidence in “Zambia, Togo, and Rwanda … increased by 7, 10, and 21 percent, respectively, every year over the 1980s,” Brinkmann and his colleagues wrote. “Thus, the burden of malaria in 1995 is likely to be two to three times its level in the late 1980s.”

  Costs included lost workdays due to prolonged bouts with the parasites; funeral expenses; hospital and drug costs; family impoverishment due to the death of a major breadwinner; and a host of other factors.

  “Overall, in 1987 the cost of malaria in sub-Saharan Africa was about $791 million per year,” the group wrote. “This figure is projected to rise to $1,684 billion by 1995. By comparison, the entire 1990 health assistance to Africa of a major bilateral donor, the U.S. Agency for International Development, was only $52 million for all conditions. In 1987 malaria represented 0.6 percent of GDP; by 1995, if current trends continue, this share will rise to 1.0 percent of GDP.” See D. S. Shepard, M. B. Ettling, U. Brinkmann, and R. Sauerborn, “The Economic Cost of Malaria in Africa,” Tropical Medicine and Parasitology 42 (1991): 199–203. See also in the same volume U. Brinkmann and A. Brinkmann, “Malaria and Health in Africa: The Present Situation and Epidemiological Trends”: 205–13; M. B. Ettling and D. S. Shepard, “Economic Cost of Malaria in Rwanda”: 214–18; and R. Sauerborn, D. S. Shepard, M. B. Ettling, et al., “Estimating the Direct and Indirect Economic Costs of Malaria in a Rural District of Burkina Faso”: 219–23.

  156 See S. C. Redd, P. B. Bloland, P. N. Kazembe, et al., “Usefulness of Clinical Case-Definitions in Guiding Therapy for African Children with Malaria or Pneumonia,” Lancet 340 (1992): 1140–43.

  157 See P. B. Bloland, E. M. Lackritz, P. N. Kazembe, et al., “Beyond Chloroquine: Implications of Drug Resistance for Evaluating Malaria Therapy Efficacy and Treatment Policy in Africa,” Journal of Infectious Diseases 167 (1993): 932–37; C. C. Campbell, P. Nguyen-Dinh, and J. G. Breman, “Epidemiological and Operational Considerations in the Use of Antimalarial Drugs for Chemotherapy and Chemoprophylaxis of Malaria in Africa,” Annals de la Société Belgique de Médecine Tropique 65 (1985): 165–70; and E. M. Lackritz, C. C. Campbell, T. K. Ruebush, et al., “Effect of Blood Transfusion on Survival Among Children in a Kenyan Hospital,” Lancet 340 (1992): 528–88;

  158 D. L. Heymann, R. W. Skeketee, J. J. Wirima, et al., “Antenatal Chloroquine Chemoprophylaxis in Malawi: Chloroquine Resistance, Compliance, Protective Efficacy and Cost,” Transactions of the Royal Society of Tropical Medicine and Hygiene 84 (1990): 496–8.

  159 Malawi Ministry of Health, “Malaria Control in Malawi, 1984–1988: Policy Modification and Program Development in Response to Chloroquine Resistance,” unpublished, 1993.

  160 S. L. Hoffman, C. N. Oster, C. V. Plowe, et al., “Naturally Acquired Antibodies to Sporozoites Do Not Prevent Malaria: Vaccine Development Implications,” Science 237 (1987): 639–42.

  161 Similar results were obtained by L. W. Pang, N. Limsomwong, J. Karwacki, and H. K. Webster, “Circumsporozoite Antibodies and falciparum Malaria Incidence in Children Living in a Malaria Endemic Area,” Bulletin of the World Health Organization 66 (1988): 359–63.

  162 A. W. Taylor-Robinson, R. S. Phillips, A. Severn, et al., “The Role of TH1 and TH2 Cells in a Rodent Malaria Infection,” Science 260 (1993): 1931–34.

  163 Y. Charoenvit, W. E. Collins, T. R. Jones, et al., “Inability of Malaria Vaccine to Induce Antibodies to a Protective Epitope Within Its Sequence,” Science 251 (1991): 668–72; J. E. Egan, J. L. Weber, W. R. Ballou, et al., “Efficacy of Murine Malaria Sporozoite Vaccines: Implications for Human Vaccine Development,” Science 236 (1987): 453–56; and R. Rosenberg, R. A. Wirtz, D. E. Lanar, et al., “Circumsporozoite Protein Heterogeneity in the Human Malaria Parasite Plasmodium vivax,” Science 245 (1989): 973–76.

  164 J. Lines and J. R. M. Armstrong, “For a Few Parasites More: Inoculum Size, Vector Control and Strain-Specific Immunity to Malaria,” Parasitology Today 8 (1992): 381–83.

  165 S. Kumar, L. H. Miller, and I. A. Quakyi, “Cytotoxic T Cells Specific for the Circumsporozoite Protein of Plasmodium falciparum,” Nature 334 (1988): 258–60; and Institute of Medicine, Malaria: Obstacles and Opportunities (Washington, D.C.: National Academy Press, 1991).

  166 S. L. Hoffman, V. Nussenzweig, J. C. Sadoff, and R. S. Nussenzweig, “Progress Toward Malaria Preerythrocytic Vaccines,” Science 252 (1991): 520–21.

  167 One theory had it that chloroquine resistance could only get so bad in a society before the humans would develop sufficient baseline immunity to keep the parasites in check. A state of tolerance developed, and the partially immune humans were able to prevent the parasites from developing complete resistance. See J. C. Koella, “Epidemiological Evidence for an Association Between Chloroquine Resistance of Plasmodium falciparum and Its Immunological Properties,” Parasitology Today 9 (1993): 105–8.

  168 D. Hurvitz and K. Hirschhorn, “Suppression of in vitro Lymphocyte Responses by Chloroquine,” New England Journal of Medicine 273 (1965): 23–26; G. Salmeron and P. E. Lipsky, “Immunosuppression Potential of Antimalarials,” American Journal of Medicine 75 (1983): 19–24; and D. N. Taylor, C. Wasi, and K. Bernard, “Chloroquine Prophylaxis Associated with a Poor Antibody Response to Human Diploid Cell Rabies Vaccine,” Lancet I (1984): 1405.

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sp; 169 M. Pappaionou, D. B. Fishbein, D. W. Dreesen, et al., “Antibody Response to Preexposure Human Diploid-Cell Rabies Vaccine Given Concurrently with Chloroquine,” New England Journal of Medicine 314 (1986): 280–84.

  The immune system dampening effect was not true for all types of immunizations. Nigerian children responded similarly to pneumococcal vaccines regardless of whether or not they took chloroquine. See C. Van Der Straeten and J. H. Klippel, “Antimalarials and Pneumococcal Immunization,” New England Journal of Medicine 315 (1986): 712.

  170 An extensive study of the use of chloroquine prophylaxis on Nigerian children in 1984 yielded a puzzling result: the prophylaxed children suffered fewer cases of malaria, but were just as likely as kids who never took chloroquine to die of malaria. In this study malaria was defined as fever plus laboratory-confirmed parasite infection of the child’s blood. Given that definition of malaria, there may be less contradiction than first meets the eye between a lower incidence of “malaria” in the chloroquineusing group and an equal or higher death rate. See A. Bradley-Moore, D. E. Bidwell, A. Voller, et al., “Malaria Chemoprophylaxis with Chloroquine in Young Nigerian Children,” Annals of Tropical Medicine and Parasitology 79 (1985): 549–62.

  171 For further evidence of the antifever effect of chloroquine, see A. D. Brandling-Bennett, A. J. Oloo, W. M. Watkins, et al., “Chloroquine Treatment of falciparum Malaria in an Area of Kenya of Intermediate Chloroquine Resistance,” Transactions of the Royal Society of Tropical Medicine and Hygiene 82 (1988): 833–37.